Muscle growth and repair is a complex process that involves the proliferation and differentiation of myoblasts which fuse with existing muscle fibers. The broad objective of this research proposal is to define the cell signaling mechanisms that regulate this process. SHP-2 is a cytoplasmic protein tyrosine phosphatase that is required for myogenesis. Our preliminary data suggests that SHP-2 is required to activate NFAT, a critical regulator of muscle growth, through the Ca2+ calcineurin and RhoA signaling pathways. We will use primary myoblasts to determine the mechanism by which SHP-2 activates Ca2+ calcineurin and RhoA signaling to regulate NFAT and myogenesis. Substrate-trapping mutants of SHP-2 and mass spectrometry will be used to identify the substrates through which SHP-2 regulates NFAT. Mice with a skeletal muscle specific deletion of SHP-2 will be used in a muscle injury model to investigate the in vivo role of SHP-2 in regulating muscle growth and regeneration. A greater appreciation for the role SHP-2 serves in regulating muscle growth and regeneration will enhance our understanding of this poorly understood facet of cell signaling and may open new avenues for therapies to treat myopathies. [unreadable] [unreadable] [unreadable]